1. Field of the Invention
The invention relates to a method for treating viral infectious diseases comprising the step of administering an effective amount of amphiphilic nucleoside-phosphonoformic acid derivatives.
Viral infections, and diseases associated therewith, constitute complications which have to be taken seriously, particularly in the case of immunosuppressed patients. Immunosuppression for the purpose of avoiding rejection reactions is required, for example, in connection with transplanting solid organs and in connection with transplanting bone marrow or stem cells. Viral infectious diseases also constitute a particular risk, which has to be taken seriously, for patients who are suffering from immune diseases such as AIDS.
Developing antiviral pharmaceuticals has proved to be extremely difficult. This is due, in particular, to the fact that viruses only replicate in host cells and, in this connection, as intracellular parasites, use the enzymes of the host in addition to viral enzymes. Because of the complex interaction of the viral genome and the metabolism of the host cell, it is scarcely possible to stop virus replication without damaging the host cell. Furthermore, many viral infections only become clinically manifest when, as a consequence of the viral infestation, the host cells have already been irreversibly damaged.
In addition to human immunodeficiency virus (HIV), some members of the Herpesviridae family, in particular, play a prominent role in infectious diseases of immunosuppressed patients, inter alia. This group includes, for example, herpes simplex virus, varicella zoster virus (VZV), Epstein-Barr virus (EBV) and (human) cytomegalovirus (HCMV).
Like the other herpes viruses, human cytomegalovirus (HCMV) persists in the host throughout life after an infection. In immunocompetent individuals, human cytomegalovirus as a rule causes an infection picture which is similar to that of Pfeiffer's glandular fever. However, Heiniger at al. report that severe symptomatic HCMV infections, in the sense of an organ disease, can occur, for example, in patients who are undergoing surgical intensive care but who are not immunosuppressed. Only a fully functional immune system is able to prevent an HCMV disease in the wake of an HCMV infection.
2. Related Prior Art
Inhibitors of protein and nucleic acid synthesis can be used for chemotherapy purposes in connection with viral infections. A major problem in this regard is the toxicity which results from affecting the cellular mechanism as well.
At present, only three antiviral active substances which are approved for treating HCMV infections in humans are available: ganciclovir (GCV), foscamet (sodium-phosphonoformic acid, PFA) and also cidofovir (CDV). Ganciclovir is an acyclic guanosine analogue and cidofovir is an acyclic deoxycytidine monophosphate (dCMP) analogue. As a salt of phosphonoformic acid, foscamet differs markedly in its structure from these nucleoside/nucleotide analogues.
All three active compounds ultimately suppress viral DNA synthesis by inhibiting the HCMV DNA polymerase. As a prodrug, 9-[1,3-dihydroxy-2-propoxymethyl]guanine (ganciclovir) has first of all to be phosphorylated to ganciclovir triphosphate in order to express its antiviral activity. For this, it is phosphorylated to ganciclovir monophosphate by an HCMV-encoded phosphotransferase (UL97) in a first step. Host cell kinases then phosphorylate this monophosphate to the triphosphate by way of the diphosphate. During viral DNA synthesis, the ganciclovir triphosphate is incorporated, as a dGTP analogue, into the nascent strand, with this leading to chain termination of the DNA replication of the HCMV.
1-[(S)-3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (cidofovir) is an acyclic nucleoside monophosphonate which has to be phosphorylated up to the triphosphate by cellular kinases in order to be converted into an active form. The phosphorylation is carried out by host enzymes and is consequently independent of virus-encoded kinases. As in the case of GCV triphosphate, incorporation of CDV triphosphate (CDV-TP) into the newly forming viral DNA strand leads to the viral DNA replication being chain-terminated.
Foscarnet (sodium-phosphonoformic acid) is a pyrophosphate analogue which does not require any initial intracellular activation. This active compound directly blocks the pyrophosphate-binding site of the viral DNA polymerase and thereby inhibits the elimination of pyrophosphate from dNTPs.
The above mentioned substances display side-effects which are in some cases substantial. The side-effects of these drugs are summarized in the publication by Crumpacker C S., “Ganciclovir”, N. Engl. J. Med. 1996, 335: 721-731).
Thus, administering ganciclovir results, in particular, in a reduction in the number of white blood cells and frequently of the platelets as well. An anaemia can also develop if the drug is administered over a relatively long period. Because of the haematological toxicity, administering the full dose of ganciclovir in combination with other myelotoxic pharmaceuticals can be life-threatening.
Cidofovir exhibits dose-dependent nephrotoxicity. The latter is elicited by a disequilibrium between rapid uptake into the cells of the proximal tubule and a slower efflux into the urine, with this leading to accumulation in the kidneys.
Foscarnet exhibits substantial renal and metabolic toxicity. The nephrotoxicity is based on direct damage to the kidney tubules.
A particularly critical situation with regard to successful therapeutic intervention arises when multiresistance to ganciclovir, foscamet and cidofovir is manifested in connection with an HCMV infection. The development of resistance is a serious clinical problem and can result in death, particularly in the case of multiresistance. In the pre-HAART (highly active antiretroviral therapy) era, it was essentially AIDS patients with HCMV retinitis who were affected by the development of GCV-resistant strains.
At present, when a ganciclovir-resistant HCMV infection is detected, foscarnet is used as alternative medication. However, a disadvantage of this approach is that a relatively high effective dose of foscarnet is required in order to achieve an efficient antiviral effect. A high effective dose in turn results in toxic side-effects. When a multiresistant HCMV infection develops, no further antiviral agents are available.
A further disadvantage of the virostatic agents which are presently available is their lack of oral bioavailability, which makes it necessary to administer them intravenously. The venous catheters which are inserted for this purpose in connection with continuous therapy can lead to sepsis.
A further problem is the limited diffusion of the highly polar virostatic agents through the blood-brain barrier into the cerebrospinal fluid space. Eckle, et al., “Drug-resistant human cytomegalovirus infection in children after allogenic stem cell transplantation may have different clinical outcomes”, Blood (2000) 96(9):3286-3289, showed that neither ganciclovir, intravenously or intrathecally, nor foscarnet or cidofovir, were able to have an effect on an HCMV encephalitis which was elicited by a multiresistant HCMV strain following a bone marrow transplantation.
WO 98/38202 discloses lipophilic phosphonoacids/nucleoside conjugates which exhibit antiviral activity. The compounds disclosed in this document include phosphonoformic acid/nucleoside conjugates, with the conjugates containing at least one lipophilic group and at least one nucleoside group.